Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors.
Blockade of Hsp90 by 17AAG antagonizes MDMX and synergizes with Nutlin to induce p53-mediated apoptosis in solid tumors.
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DOI：
10.1038/cddis.2011.39
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发表时间：
2011-05-12
影响因子：
9
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中科院分区：
文献类型：
--
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在保留p53的肿瘤中诱导p53激活的策略在癌症治疗中具有很高的潜力。Nutlin是一种高效的高选择性MDM2抑制剂，可诱导非遗传毒性的P53激活。尽管Nutlin在促进血液系统恶性肿瘤的细胞死亡方面表现出了希望，但一个主要的障碍是，大多数实体癌症不会发生凋亡，而只是可逆的生长停滞。未被对抗的MDMX对P53的抑制是导致细胞对Nutlin耐药的主要原因之一。Hsp90伴侣在癌细胞中普遍激活，并支持致癌生存途径，其中许多途径拮抗P53。Hsp90抑制剂17-烯丙氨基-17-去甲氧基格尔达那霉素(17AAG)可诱导P53依赖的细胞凋亡。我们在这里展示了在多个难以杀死的实体瘤细胞中，17AAG调节几个关键成分，这些关键成分与Nutlin激活的P53信号协同作用，在体外和异种移植瘤中将Nutlin的瞬时细胞抑制反应转化为细胞毒性杀伤反应。与Nutlin结合，17AAG破坏MDMX的稳定，减少MDM2，诱导PUMA，并抑制癌基因生存途径，如PI3K/AKT，在多个水平上对抗P53信号。从机制上讲，17AAG通过诱导MDMX的降解来干扰抑制MDMX-P53轴，从而显著增加P53的转录。据我们所知，Nutlin+17AAG代表了MDMX的第一个有效的药理敲除。我们的研究确定17AAG是一种更有效的基于Nutlin的治疗的有前途的合成致命伙伴。
Strategies to induce p53 activation in wtp53-retaining tumors carry high potential in cancer therapy. Nutlin, a potent highly selective MDM2 inhibitor, induces non-genotoxic p53 activation. Although Nutlin shows promise in promoting cell death in hematopoietic malignancies, a major roadblock is that most solid cancers do not undergo apoptosis but merely reversible growth arrest. p53 inhibition by unopposed MDMX is one major cause for apoptosis resistance to Nutlin. The Hsp90 chaperone is ubiquitously activated in cancer cells and supports oncogenic survival pathways, many of which antagonize p53. The Hsp90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG) is known to induce p53-dependent apoptosis. We show here that in multiple difficult-to-kill solid tumor cells 17AAG modulates several critical components that synergize with Nutlin-activated p53 signaling to convert Nutlin's transient cytostatic response into a cytotoxic killing response in vitro and in xenografts. Combined with Nutlin, 17AAG destabilizes MDMX, reduces MDM2, induces PUMA and inhibits oncogenic survival pathways, such as PI3K/AKT, which counteract p53 signaling at multiple levels. Mechanistically, 17AAG interferes with the repressive MDMX–p53 axis by inducing robust MDMX degradation, thereby markedly increasing p53 transcription compared with Nutlin alone. To our knowledge Nutlin+17AAG represents the first effective pharmacologic knockdown of MDMX. Our study identifies 17AAG as a promising synthetic lethal partner for a more efficient Nutlin-based therapy.
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